Pyrazolo(1.5-a) pyridine derivatives

ABSTRACT

The present invention provides 2-substituted-3nitrosopyrazolo(1,5-a)pyridines expressed by the general formula,   WHERE X stands for a halogen atom, a lower alkoxy, hydroxy or acetoxy group, and a method for synthesizing the same. The substances of this invention expressed by the general formula (I) exhibit excellent antimicrobial action for example, the tubercle bacillus in vitro and are especially efficacious as medicine for trichomanas disease and supparative inflammation.

UIlltGd States Patent 1 [111 3,718,656

Okamoto et al. 51 Feb. 27, 1973 54] PYRAZOL0(l.5-A) PYRIDINE PrimaryExaminerAlan L. Rotman DERIVATIVES Attorney-Toren & McGeady I [75]Inventors: Toshihiko Okamoto, Bunkyo-ku,

Tokyo; Masaaki Hirobe, Setagaya- [57] ABSTRACT y Seigo ltabaShi-klf, Thepresent invention provides 2-substituted-3- q y Yoshi" Nagatsll,UYaWa'ShI, nitrosopyrazolo[ l,5a]pyridines expressed by the Saitama-ken;Kelichi Ushiyama, generalformula Minamisaitama-gun, Saitama-ken; SusumuSatoh, Kita-ku, Tokyo; Tsutomu lrikura, Nerima-ku, Tokyo, all of Japan[73] Assignee: Kyorin Seigaku Kabushiki Kaisha,

Tokyo, Japan [22] Filed: April 8, 1971 [21] Appl. No.: 132,558

[30] Foreign Application Priority Data where X stands for a halogenatom, a lower alkoiry,

hydroxy or acetoxy group, and a method for synthesiz- Sept. 25, 1970Japan ..45/83985 the same The ubstances of this invention ex pressed bythe general formula (I) exhibit excellent -260/295 260/296 H, 424/263antimicrobial action for example, the tubercle bacillus 424/266 in vitroand are especially efficacious as medicine for [51] Int. Cl. ..C07d31/34, C07d 31/42 trichomanas disease and supparative inflammation [58]Field of Search ..260/295 F, 296 H 9 Claims, No Drawings PYRAZOLOU .S-A)PYRIDINE DERIVATIVES DETAILED EXPLANATION OF INVENTION X No where Xstands for a halogen atom, lower alkoxy, hydroxy or acetoxy group.

As a method to introduce a nitroso group to the 3- position ofpyrazolo[1,5-a]pyridines expressed by the general formula (II), thegenerally employed method of direct nitrosation is preferred in which amore than equimolar amount of nitrosation agent selected from the groupconsisting of nitrous acid, sodium and potassium salts of nitrous acid,ethyl, butyl and amyl ester of nitrous acid and nitrosyl chloride isreacted in water or an organic solvent containing acetic acid or amineral acid.

The raw material of this invention as described above, expressed by thegeneral formula (II), is a novel compound and is prepared by the Bowersprocess (J. Chem. Soc., 4510 (1957) or by the process newly developed bythe present inventors in which a Schiff base of 1-amino-2-picaliniumsalt is oxidized for ring formation or l-acylimido-Z-picoline isdehydrated for ring formation.

2-Substituted-3-nitrosopyrazolo[ 1 ,5-a]pyridines, prepared as mentionedabove, expressed by the general formula (1) exhibit excellentantimicrobial action for example, the tubercle bacillus in vitro and areespecially efficacious as medicine for trichomonas disease andsuppurative inflammation as shown in the following table.

ANTIBACTERIAL TEST OF 2-Substituted-3-nitrosopyrazolo[ 1 ,5-a]pyridine(1) (minimum concentration for growth inhibition, 'y/ml) Compounds B. P.T. of subtilis aureus chrysofoetus tuberculosis this 1189 genus Aoyamai)r(ivention B strain 1. meta-Cl 0.5 1 1 0.4 1 2. meta-Br 1 S 5 2 3.para-Cl 0.2 0.78 10 2 2.5

4. para-Br 1 5. para-OH 5 6. para- 5 O.C0.CH,

7. ortho- OCH,

8. meta- 1 5 l 2 l OCH, 1 Compounds for Comparison 9. (Anti-tubercularmedicine) Ethionamide 10. Medicine of trichomonas disease) MetronidazoleExample 1 300 Milligrams (0.0013 mole) of2-(p-chlorophenyl)pyrazolo[1,5a]pyridine was dissolved in 8ml of glacialacetic acid and 1.8m1 (0.0013 mole) of an aqueous solution of sodiumnitrite (lg of the compound in 20ml of water) was added dropwise at theroom temperature under stirring. Stirring was continued for additional 2hours, then yellowish green crystals deposited were separated byfiltration, dissolved in 20ml chloroform, washed with an aqueoussolution of sodium carbonate and dried with anhydrous sodium sulfate.When chloroform was distilled bluish green crystals were obtained.Recrystallization from benzene gave 200mg (60 percent) of 2-(pchlorophenyl)-3-nitrosopyrazolo[1,5- a]pyridine as green needles.Melting point: 201.5 202.5C.

Analysis: as C l-l N OCl Calculated; C: 60.59% H: 3.13% N: 16.31%

Found; C: 60.38% H: 3.36% N: 16.67%

EXAMPLE 2 2-(p-Bromophenyl)pyrazolo[ 1 ,5-a]pyridine was reacted andtreated in the same manner as in Example 1 and2-(p-bromophenyl)-3-nitrosopyrazolo[1,5 a]pyridine was obtained. Meltingpoint: 198 199C, yield: 93 percent.

Analysis: as C l'l N oBr Calculated; C: 51.68% H: 2.67% N: 13.91%

Found;C: 51.60% H: 2.75% N: 13.86%

Example 3 Z-(m-Bromophenyl)pyrazo1o[1,5-a]pyridine was reacted andtreated in the same manner as in Example 1 and2-(m-bromophenyl)-3-nitrosopyrazolo|1,5- a]pyridine was obtained.Melting point: 209 2| 1C, yield: 64 percent.

Analysis: as c l-l N OBr Calculated; C: 5 1 .68% H: 2.67% N: 13.91%

Found;C: 51.65% H: 2.82% N: 13.80%

Example 4 2-(o-Methoxyphenyl)pyrazolo[ l ,5-a]pyridine was reacted andtreated in the same manner as in Example 1 andZ-(o-methoxyphenyl)-3-nitrosopyrazolo[1,5- a]pyridine was obtained.Melting point: 144 145C, yield: 73 percent.

Analysis: as C l-l N O Calculated; C: 66.39% H: 4.38% N: 16.59%

Found; C: 66.14% H: 4.22% N: 16.56%

Example 5 2-(m-Chlorophenyl)pyrazolo[1,5-a]pyridine was reacted andtreated in the same manner as in Example 1 and2-(m-chlorophenyl)-3-nitrosopyrazolo[1,5-

a]pyridine was obtained. Melting point: 215 216C, yield: 90 percent.

Analysis: as C H N OCl Calculated; C: 60.59% H: 3.13% N: 16.31%

Found; C: 60.33% H: 3.28% N: 16.55%

Example 6 2-(p-Acetoxyphenyl)pyrazolo[1,5-a]pyridine was reacted andtreated in the same manner as in Example 1 andZ-(p-acetoxyphenyl)-3-nitrosopyrazolo[l,5- alpyridine was obtained.Melting point: 188 189C, yield: 89 percent.

Analysis: as C ,,H,,N O

Calculated: C: 64.05% H: 3.94% N: 14.94%

Found: C: 64.12% H: 3.83% N: 15.12%

Example 7 2-(p-Hydroxypehnyl)pyrazolo[ l ,5-a]pyridine was reacted andtreated in the same manner as in Example 1 andZ-(p-hydroxyphenyl)-3-nitrosopyrazo1o[1,5- a]pyridine was obtained.Melting point: 266 270C, yield: 92 percent.

Analysis: as C H N Calculated: C: 65.26% H: 3.78% N: 17.57%

Found: C: 65.50% H: 3.85% N: 17.37%

Example 8 2-(m-Methoxyphenyl)pyrazolo[ 1,5-a]pyridine was reacted andtreated in the same manner as in Example 1 and2-(m-methoxyphenyl)-3-nitrosopyrazolo[1,5- a]pyridine was obtained.Melting point: 152 154C, yield: 81 percent.

Analysis: as C H N O Calculated: C: 66.39% H: 4.38% N: 16.59%

Found: C: 66.21% H: 4.21% N: 16.44%

Example 9 A mixture of 3.47g of 1-(m-chlorobenzalamino)-2- picoliniumiodide (111: X m-Cl; mp. 179 180C, yellow needles from EtOH) and 2.5g ofiodine in 50ml of pyridine was refluxed for 4 hr. After removal of theexcess reagents, the resulting dark mass was chromatographed on silicagel using benzene as eluent to give 1.49g of2-(m-chlorophenyl)pyrazolo[l,5-a]pyridine, which was recrystallized fromAcOEt as colorless needles, mp. 128- 129C.

The same treatment of l-( various substituted benzalamino)-2-pico1iniumiodides (111) as for l-(mchlorobenzalamino)-2-picolinium iodide (111: Xm- Cl) gave 2-( various substituted phenyl)pyrazolo[ 1,5-a] pyridines(11) as shown in the following Table.

(111) "a (ll) Recryst. Yield x mpmj) mp(=C) solvent of 11 p-Cl 176-177178-179 AcOEt 43% p-Br 161-164 193-194 AcOEt 52% m-Br 154-157 116-118AcOEt 48% o-CH,0 158-160 011 p-CH,COO 142-143 AcOEt 98% "b p-HO 196-197204-205 MeOH 27% m-CH,O 149-152 65-66 MeOH 62% 'a) recrystallized fromEtOH as pale yellow needles b) prepared by the reaction of 11(X= p-OH)with acetic anhydride Example 10 To an ice-cooled solution of 2.46g ofl-(mchlorobenzoylimino)-2-picoline (mp. 88C, colorless needles fromAcOEt-n-hexane) in 38ml of pyridine was added gradually 3.8ml of POClAfter the addition was 1 ILJNO X where X stands for a halogen atom, alower alkoxy, hydroxy or acetoxy group.

2. 2-(p-Chlorophenyl)-3-nitrosopyrazolo [1,5-a] pyridine.

3. 2-(p-Bromopheny1)-3-nitrosopyrazolo [1,5-a] pyridine.

4. 2-(m-Bromophenyl)-3-nitrosopyrazolo [1,5-a] pyridine.

5. 2-(o-Methoxyphenyl)-3-nitrosopyrazolo [1,5-a] pyridine.

6. 2-(m-Chlorophenyl)-3-nitrosopyrazolo [1,5-a] pyridine.

7. 2-(p-Acetoxyphenyl)-3-nitrosopyrazolo [1,5-a] pyridine.

8. 2-(p-Hydroxyphenyl)-3-nitrosopyrazolo [1,5-a]

pyridine.

9. Z-(m-Methoxyphenyl)-3-nitrosopyrazolo pyridine.

* i i i

2. 2-(p-Chlorophenyl)-3-nitrosopyrazolo (1,5-a)pyridine. 3.2-(p-Bromophenyl)-3-nitrosopyrazolo (1,5-a)pyridine. 4.2-(m-Bromophenyl)-3-nitrosopyrazolo (1,5-a)pyridine. 5.2-(o-Methoxyphenyl)-3-nitrosopyrazolo (1,5-a)pyridine. 6.2-(m-Chlorophenyl)-3-nitrosopyrazolo (1,5-a)pyridine. 7.2-(p-Acetoxyphenyl)-3-nitrosopyrazolo (1,5-a)pyridine. 8.2-(p-Hydroxyphenyl)-3-nitrosopyrazolo (1,5-a)pyridine. 9.2-(m-Methoxyphenyl)-3-nitrosopyrazolo (1,5-a)pyridine.